More Americans are overweight or obese than are within the ideal weight range. Bariatric surgery is the only effective long-term treatment for obesity, but it does not reduce health care costs and the life-long consequences of this invasive surgery have yet to be fully elucidated. Therefore, development of effective, non surgical strategies for prevention and reversal of weight gain is essential. Leptin was identified as a negative feedback signal in the regulation of energy balance in 1994, but little progress has been made using leptin to prevent or reverse human obesity. This may be due in part to the pharmacologic nature of many studies designed to investigate an endogenous physiologic mechanism. In this proposal we use near-physiologic doses of leptin that initiate a response only when leptin receptors (ObRb) in both the forebrain and hindbrain are activated. Doses of leptin too low to influence energy balance when infused into either the 3rd or the 4th ventricle separately, reduce body fat by 75% in 12 days when given simultaneously. Food intake is initially inhibited by 40-60%, but is not different from controls after 6 days. Additional data sho that activation of ObRb in the hindbrain facilitates phosphorylation of signal transducer and transcription 3 (pSTAT3) in the forebrain. pSTAT3 is required for leptin induced changes in energy balance and is an accepted marker of ObRb activation. These data strongly support the hypothesis that simultaneous activation of ObRb in the forebrain and hindbrain is required for leptin to induce a state of negative energy balance. We propose that activation of hindbrain ObRb lowers the threshold for activation of forebrain ObRb, priming the nuclei to respond to subtle elevations in central leptin when circulating leptin rises in parallel with increased body ft. This results in a very sensitive feedback system for the control of energy balance. Aim One of this proposal will confirm and extend pilot data that hindbrain leptin infusion lowers the threshol of response to 3rd ventricle leptin and test whether sensitization of the hypothalamus is mediated by a neural mechanism or is caused by leptin diffusing from the 4th into the 3rd ventricle. Aim Two will test whether increased hypothalamic pSTAT3 is limited to cells that express ObRb, test whether 4th ventricle leptin infusion activates areas of the forebrain that do not express STAT3 and identify hypothalamic nuclei that are essential for leptin-induced weight loss. Taken together these Aims will provide new and impactful information on a sensitive and precise system for the control of energy balance. They also will provide novel information on the integration of hindbrain and hypothalamic neural activity.